MUC1 decoy peptides for treatment and prevention of bacterial infections

Abstract

Pseudomonas aeruginosa flagellin protein recruits the mammalian host sialidase enzyme neuraminidase-1 (NEU1) to remove sialic acid residues from the extracellular domain of the mammalian cell-surface protein MUC1 (MUC1-ED), thereby exposing a cryptic binding site on the MUC1-ED protein backbone for flagellin binding. NEU1-driven MUC1-ED desialylation rapidly increases P. aeruginosa adhesion to the airway epithelium. MUC1-ED desialylation also increases MUC1-ED cleavage and shedding from the cell surface, where desialylated, shed MUC1-ED competitively blocks P. aeruginosa adhesion to cell-associated MUC1-ED. Presented herein are data showing that exogenously-administered, deglycosylated MUC1-ED peptides reduced adhesion of P. aeruginosa to airway epithelial cells. Also presented are data showing that administration of P. aeruginosa to mice in combination with deglycosylated MUC1-ED decreased P. aeruginosa recovered from the lungs at 48 hr and 72 hr post-infection. Such findings are extended to the methods of treatment and prevention of bacterial infections defined herein.

What is claimed is: 
     
       1. A method of treating or preventing a pulmonary infection caused by  Pseudomonas aeruginosa  in a subject, comprising administering to the subject a therapeutically effective amount of an ectodomain MUC1 decoy peptide comprising the amino acid sequence set forth in SEQ ID NO:3. 
     
     
       2. The method of  claim 1 , wherein the pulmonary infection is treated. 
     
     
       3. The method of  claim 1 , wherein the pulmonary infection is an infection of the lungs of a subject with cystic fibrosis or a ventilator-associated pneumonia. 
     
     
       4. The method of  claim 1 , wherein the ectodomain MUC1 decoy peptide is formulated in a pharmaceutical formulation comprising the peptide and a pharmaceutically acceptable carrier or diluent. 
     
     
       5. The method of  claim 1  further comprising administering a therapeutically effective amount of one or more antibiotics to the subject. 
     
     
       6. The method of  claim 5 , wherein the one or more antibiotics are formulated in a pharmaceutical formulation comprising the antibiotic and a pharmaceutically acceptable carrier or diluent. 
     
     
       7. The method of  claim 5  wherein the ectodomain MUC1 decoy peptide comprises the amino acid sequence set forth in SEQ ID NO:3 the antibiotic is cefepime. 
     
     
       8. The method of  claim 5  wherein the ectodomain MUC1 decoy peptide and the one or more antibiotics are administered to the subject via separate administrations. 
     
     
       9. The method of  claim 1 , wherein the administering comprises administering by inhalation.